RESUMO
Acute gastrointestinal graft-versus-host disease (GVHD) refractory to first-line treatment with systemic corticosteroids results in increased morbidity and potential mortality. We retrospectively assessed the feasibility and efficacy of catheter-directed intra-arterial platelet infusion (IAPI) in two pediatric patients with steroid and transfusion refractory gastrointestinal GVHD causing intractable lower gastrointestinal hemorrhage and refractory thrombocytopenia, that were referred for salvage therapy. Immediate angiographic response was noted with a resolution of hemorrhage and decreased blood requirements. We reviewed the literature regarding this treatment modality and compared it to the available minimally invasive transcatheter techniques to control gastrointestinal hemorrhage.
Assuntos
Hemorragia Gastrointestinal/terapia , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas , Transfusão de Plaquetas , Trombocitopenia/terapia , Criança , Feminino , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/patologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Masculino , Trombocitopenia/etiologia , Trombocitopenia/patologiaRESUMO
The clinical goal of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to minimize GVHD while maintaining GvL. Here, we show that interferon γ receptor-deficient (IFNγR(-/-)) allogeneic Tconv, which possess normal alloreactivity and cytotoxicity, induce significantly less GVHD than wild-type (WT) Tconv. This effect is mediated by altered trafficking of IFNγR(-/-) Tconv to GVHD target organs, especially the gastrointestinal (GI) tract. We show that the chemokine receptor CXCR3 is induced via IFNγR-mediated signaling and partially contributes to the trafficking of WT Tconv to GVHD target organs. Indeed, CXCR3(-/-) Tconv recapitulate the reduced GVHD potential of IFNγR(-/-) Tconv in a minor-mismatched GVHD model. Most importantly, IFNγR(-/-) (and CXCR3(-/-)) Tconv mediate a robust and beneficial GvL effect. In addition, we show that IFNγR(-/-) regulatory T cells (Tregs) are fully suppressive in vitro although defective in suppressor function in vivo and that WT Tregs suppress GVHD in vivo only when allogeneic Tconv produce interferon γ (IFNγ), suggesting that the IFNγR signaling pathway is the major mechanism for both Tregs and Tconv to migrate to GVHD target organs. Finally, pharmacologic inhibition of IFNγR signaling with inhibitors of JAK1/JAK2, which are mediators of IFNγR signaling, results in the decreased expression of CXCR3 and reduced GVHD and improved survival after allo-HSCT and this effect is mediated by altered trafficking of Tconv to GVHD target organs.
Assuntos
Movimento Celular/imunologia , Doença Enxerto-Hospedeiro/imunologia , Receptores de Interferon/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Células Cultivadas , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Camundongos , Camundongos Transgênicos , Nitrilas , Pirazóis/farmacologia , Pirimidinas , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Receptores CXCR3/metabolismo , Receptores de Interferon/genética , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Transplante Homólogo/efeitos adversos , Transplante Homólogo/imunologia , Receptor de Interferon gamaRESUMO
Herbaspirillum species, an organism commonly found in soil, has only recently been linked to disease in humans. We report Herbaspirillum bacteremia in a 2-year-old female patient following a hematopoietic stem cell transplant for relapsed acute lymphoblastic leukemia.
Assuntos
Bacteriemia/diagnóstico , Infecções por Bactérias Gram-Negativas/diagnóstico , Herbaspirillum/isolamento & purificação , Hospedeiro Imunocomprometido , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Bacteriemia/microbiologia , Pré-Escolar , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Feminino , Infecções por Bactérias Gram-Negativas/microbiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Filogenia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Transplante HomólogoRESUMO
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often complicated by alloreactive donor T-cell-mediated graft-versus-host disease (GvHD). The major polyphenol of green tea, epigallocatechin-3-gallate (EGCG), is an inhibitor of both DNA methyltransferase 1 (DNMT1) and signal transducer and activator of transcription 1 (STAT1), which are essential for induction of GvHD. Thus, in this report, we examine if in vivo administration of EGCG mitigates GvHD in several different animal models. While we concede that refinement of EGCG treatment might result in GvHD prevention, our results suggest that EGCG treatment might not be an effective therapy against GvHD in the clinic.